Our long-term goal is to define the cellular and molecular mechanisms by which mutations in presenilins (PS1 and PS2) cause dementia and neurodegeneration in Alzheimer's disease (AD) and frontotemporal dementia (FTD). To characterize the normal physiological role of presenilins in the adult cerebral cortex, where AD and FTD pathogenesis manifest, we generated conditional knockout (cKO) mice, in which expression of either PS1 alone or both PS is selectively inactivated in the postnatal forebrain. Analysis of PS1 cKO mice showed that PS1 is required for normal processing of the amyloid precursor protein, generation of amyloid peptides, and hippocampal spatial memory. Our recent studies of PS1 and PS2 conditional double knockout (PS cDKO) mice demonstrated that inactivation of both presenilins in the postnatal forebrain results in memory and synaptic plasticity impairments followed by progressive, substantial neurodegeneration. Furthermore, we identified selective reductions in the transcriptional expression of CREB binding protein (CBP) and CREB/CBP target genes as well as in the synaptic levels of NMDA receptor subunits and aCaMKII in PS cDKO mice. We therefore hypothesize that impairments in synaptic plasticity caused by loss of PS function promote progressive neurodegeneration in the cerebral cortex. In this competing renewal application, we propose to investigate further the cellular and molecular mechanisms by which presenilins regulate synaptic plasticity. We will first use the forebrain-restricted PS cDKO mice to look for additional presynaptic deficits in probability of neurotransmitter release, to establish the temporal course of the pre- and post- synaptic plasticity impairments, and to identify alterations in the ultrastructure of the synapse and in the levels of key pre- and post-synaptic proteins implicated in synaptic plasticity. We will also investigate how PS regulate transcriptional expression of CBP, and whether CBP plays an essential role in memory and synaptic plasticity. We will then generate hippocampal area CA1 or CA3- restricted PS cDKO mice to determine whether selective inactivation of PS either post- or pre-synaptically in the Schaeffer collateral pathway causes impairments in synaptic plasticity and subsequent neurodegeneration. The significance of our proposed study is that a better understanding of the mechanisms by which presenilins regulate synaptic plasticity and neuronal survival will provide important insights into the pathogenesis of AD and FTD. Furthermore, identification of the molecular pathways regulated by PS may provide novel therapeutic targets for combating cognitive dysfunction and neurodegeneration in these disorders.